PROJECT SUMMARY There is an urgent need to develop vaccines that are effective in schistosome-endemic areas, such as sub-Saharan Africa, where HIV infection is common; schistosome co-infection can significantly impair the ability of people to control HIV viral load (1), therefore, functional HIV vaccines are desperately needed. It is important to dissect the mechanisms by which the Listeria vaccines are effective during chronic helminth infection to bypass the requirement of a live bacterial vaccine vector. Our central question for this preliminary data-generating proposal is: Why do Listeria vaccine vectors function when DNA vaccine vectors do not? Our long-term goal is to generate cell-mediated vaccine immunity in schistosome-infected, immune-suppressed patients. The financial rationale for this project is that millions, perhaps billions, of dollars being spent to develop effective vaccines that target all manner of infectious diseases despite very few vaccines being approved for human use. Here, we investigate why DNA vaccine vectors fail during chronic schistosomiasis when Listeria vaccine vectors can generate robust CTL responses to HIV Gag. We hypothesize that Listeria has at least one unique immunostimulatory molecule that induces Tc1 immunity during chronic schistosomiasis. Listeria monocytogenes is a live Gram-positive intracellular pathogen expressing HIV Gag from its chromosome. The objective of the proposed research is to identify which characteristic/s of Listeria vectors will adjuvant vaccines to function during chronic schistosomiasis. The scientific rationale for the proposed research is that Listeria vectors can generate robust vaccine responses after only a few minutes within a host, suggesting the initial interaction with the immune system can be replicated by exogenously delivered factors. We plan to test our central hypothesis and, thereby, accomplish the objective of this application by pursuing the following specific aims: (1) Examination of live bacteria as adjuvants for episomally expressed DNA vaccine for HIV Gag, (2) Assessment of live bacteria as adjuvants for concurrently administered DNA vaccines for HIV Gag, and (3) Evaluation of heat-killed bacteria as adjuvants for concurrently administered DNA vaccines for HIV Gag. The expected outcome of these aims will be differential results, such that we can understand which characteristic of the Listeria vector is exerting the adjuvant function. Such results are expected to have a positive impact, because if causal mediators/pathways are identified, we could successfully vaccinate immune-suppressed populations while bypassing administration of live vaccine vectors. This work is significant because it can generate a candidate adjuvant molecule effective in schistosome-endemic areas populations. Further, this research project is innovative, as it proposes to discover/develop adjuvants specifically for use in populations in schistosome- endemic areas.